Polymers which undergo reversible phase transformation are most widely used for the development of pharmaceutical formulations. Especially polymers with pH dependent dissolution behavior are getting much attention. These polymers are capable of suppressing the drug release at one pH and releasing the same at another pH.
The copolymer of 2-dimethylaminoethyl methacrylate, butylmethacrylate and methyl methacrylate is readily soluble in gastric fluid wherein the pH is <5.0. However, this polymer is permeable to the aqueous medium of pH>5.0 which limits its application as a moisture protective coating for pharmaceutical dosage forms. Particularly, in the development of oral suspensions wherein the drug encapsulated polymer particles are being suspended in reconstituted medium at pH˜5.5. If the polymer is permeable to this medium, the encapsulated drug can leach out and may lead to bitter taste for the formulation. Such polymers are also found to be useful as a rumen protective coating for drug and other feed supplements of the ruminants. Such coated compositions are capable of protecting the active agents from degradation by microorganism present in the rumen and releasing the content in the digestive system. Also the rapid dissolution of the polymer at acidic pH, limits its utility in the development of extended release formulations.
Reference may be made to patent “EP 1334986 A2” wherein Rodrigues et al. disclosed a graft copolymer which comprised either a hydrophobic backbone and amine graft chains or vice versa. The said graft copolymers are insoluble at the pH of >8.0 and they dissolved when the pH was reduced to <8.0. Since these polymers are readily dissolved at the pH of <8.0, they can not be used either as a moisture protective coating or as an excipient for the extended release formulation.
Reference may be made to Journal “Christopher D. Batich, Jun Yan, Charles Bucaria Jr. and Maher Elsabeer, Macromolecules, 26, 4675, 1993” wherein a crosslinked pH sensitive copolymer comprised styrene, 2 or 4-vinylpyridine and divinylbenzene is disclosed. The polymer was prepared in the form of beads by suspension polymerization. The pH dependent swelling behavior of the polymer was studied to explore its application in the field of drug delivery. The swelling of the polymer was not significant at pH>5 and the extent of swelling at pH<5 depended on the 2 or 4-vinylpyridine and divinylbenzene content of the polymer.
References may be made to Journals “Polymer, 43, 1533, 2002; Kim et al in Polymer Journal, 37, 565, 2005; Brahim et al in Biomacromolecules, 4, 497, 2003; Yanfeng et al in Radiation Physics and Chemistry, 61, 65, 2001 and Traitel et al in Biomaterials, 21, 1679, 2000” wherein crosslinked pH sensitive polymers are disclosed. Ratering et al. described a resin composition as a cocatalyst for the oxidative coupling of 2-mercaptoethanol [Quaternised poly(4-vinylpyridine) anchored on a macroporous poly(trimethylolpropane trimethacrylate-methylmethacrylate) resin, as cocatalyst in the cobaltphthalocyanine catalysed oxidative coupling of 2-mercaptoethanol by M. T. Ratering, et al in Reactive Polymers, 19, 233, 1993]. The resin was prepared by crosslinking copolymerization of methyl methacrylate and trimethylolpropane trimethacrylate. 4-vinypyridine monomer was grafted on the resin by reacting with unreacted residual unsaturations of trimethylolpropane trimethacrylate. The 4-vinyl pyridine graft chains of the resin were quaternised and used as catalyst. Similarly, a highly crosslinked copolymer comprising an amino monomer and a crosslinker was reported by Kempe et al. in U.S. Pat. No. 5,656,707. It has been claimed that the developed polymer is useful as a support in solid phase organic synthesis.
It is evident from the above disclosures that the currently available pH sensitive polymers swell or dissolve to some extent at the neutral and basic pH. Hence the coating of such polymers on the drug delivery formulations leads to penetration of the moisture. This is not desirable especially for the drugs which undergo transformation to their inactive form due to the presence of moisture on storage. Hence, these polymers can not be effective as a moisture protective coating. Similarly, in the case of oral suspension, the penetration of moisture into the polymer coated drug particles may lead to leaching of drug in the reconstitution medium. This gives unfavorable taste for the formulations which reduces the patient compliance. Also, these polymers are rapidly dissolved in the acidic pH medium prevalent in the stomach. Such rapid dissolution behavior limits their utility in the development extended release formulations especially gastroretentive dosage forms.
Moreover, the above disclosures also show the availability of numerous pH dependent crosslinked polymers. However, these polymers swell in both acidic and basic pH medium. Only the extent of swelling is different with respect to pH. These polymers are chemically crosslinked and hence they are not soluble in solvents. As a result the reported hydrogels have limited processability. Especially they can not be processed to obtain a film coating over the drug delivery formulations.
Also the drug loading into the hydrogel is a critical process. It is loaded either by adding the drug in the reaction mixture of hydrogel or by soaking the synthesized hydrogel in the drug solution. When the drug is loaded during the hydrogel preparation, the removal of unreacted components is critical as it leads to leaching of loaded drug. On the other hand, the loading of drug by imbibition method is time consuming and achievable, loading is very low. Such lower drug loadings are not desirable as the amount of polymer needed would be very large, possibly not meeting regulatory requirements. This limits the utility of hydrogels in the development of extended release formulations. Thus there is a need identified from the art for pH dependent polymer which is impermeable to neutral pH medium and swells/dissolves at the acidic pH prevalent in the stomach.
Further, there is also a need for polymer which is impermeable to the near neutral pH conditions and dissolves to release the content under the acidic pH conditions, which is useful for the development of oral liquid suspension comprising a bitter drug.
Such polymer will find use amongst other applications, as a protective coating material for pharmaceutical dosage form and as an excipient in the development of extended release formulations. The present invention discloses such a graft copolymer.